Targeting the CALR interactome in myeloproliferative neoplasms

• DOI: 10.1172/jci.insight.122703
• Publication Date: 2018-11-14T16:01:38Z
• Authors: Elodie Pronier; Paolo Cifani; Tiffany R. Merlinsky; Katharine Barr Be...; Amritha Varshini ...; Raajit K. Rampal; John LaCava; Karen E. Wei; Friederike Pastore; Jesper L.V. Maag; Jane Park; Richard Koche; Alex Kentsis; Ross L. Levine
• Keywords: Interactome; Myeloproliferative neoplasm; Panobinostat

Mutations in the ER chaperone calreticulin (CALR) are common myeloproliferative neoplasm (MPN) patients, activate thrombopoietin receptor (MPL), and mediate constitutive JAK/STAT signaling. The mechanisms by which CALR mutations cause myeloid transformation incompletely defined. We used mass spectrometry proteomics to identify CALR-mutant interacting proteins. Mutant caused mislocalization of binding partners increased recruitment FLI1, ERP57, MPL promoter enhance transcription. Consistent with a critical role for CALR-mediated activation, we confirmed efficacy JAK2 inhibition on cells vitro vivo. Due altered interactome induced mutations, hypothesized that MPNs may be vulnerable disruption aberrant protein complexes. A synthetic peptide designed competitively inhibit carboxy terminal specifically abrogated MPL/JAK/STAT signaling cell lines primary samples improved JAK kinase inhibitors. These findings reveal what our knowledge is novel potential therapeutic approach patients MPN.